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Human B-cell isotype switching origins of IgE - 05/02/16

Doi : 10.1016/j.jaci.2015.07.014 
Timothy J. Looney, PhD a, Ji-Yeun Lee, BS a, Krishna M. Roskin, PhD a, Ramona A. Hoh, PhD a, Jasmine King, BS a, f, Jacob Glanville, BA a, b, Yi Liu, PhD a, c, Tho D. Pham, MD a, Cornelia L. Dekker, MD d, Mark M. Davis, PhD e, g, h, Scott D. Boyd, MD, PhD a,
a Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif 
b Program in Immunology, Transplantation and Infection, Stanford University, Stanford, Calif 
c Biomedical Informatics Training Program, Transplantation and Infection, Stanford University, Stanford, Calif 
d Department of Pediatrics, Transplantation and Infection, Stanford University, Stanford, Calif 
e Department of Microbiology & Immunology, Transplantation and Infection, Stanford University, Stanford, Calif 
f Department of Biology, Transplantation and Infection, Stanford University, Stanford, Calif 
g Howard Hughes Medical Institute, Transplantation and Infection, Stanford University, Stanford, Calif 
h Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, Calif 

Corresponding author: Scott D. Boyd, MD, PhD, Department of Pathology, Stanford University, Stanford, CA 94305.

Abstract

Background

B cells expressing IgE contribute to immunity against parasites and venoms and are the source of antigen specificity in allergic patients, yet the developmental pathways producing these B cells in human subjects remain a subject of debate. Much of our knowledge of IgE lineage development derives from model studies in mice rather than from human subjects.

Objective

We evaluate models for isotype switching to IgE in human subjects using immunoglobulin heavy chain (IGH) mutational lineage data.

Methods

We analyzed IGH repertoires in 9 allergic and 24 healthy adults using high-throughput DNA sequencing of 15,843,270 IGH rearrangements to identify clonal lineages of B cells containing members expressing IgE. Somatic mutations in IGH inherited from common ancestors within the clonal lineage are used to infer the relationships between B cells.

Results

Data from 613,641 multi-isotype B-cell clonal lineages, of which 592 include an IgE member, are consistent with indirect switching to IgE from IgG- or IgA-expressing lineage members in human subjects. We also find that these inferred isotype switching frequencies are similar in healthy and allergic subjects.

Conclusions

We found evidence that secondary isotype switching of mutated IgG1-expressing B cells is the primary source of IgE in human subjects, with lesser contributions from precursors expressing other switched isotypes and rarely IgM or IgD, suggesting that IgE is derived from previously antigen-experienced B cells rather than naive B cells that typically express low-affinity unmutated antibodies. These data provide a basis from which to evaluate allergen-specific human antibody repertoires in healthy and diseased subjects.

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Key words : IgE, isotype switching, direct, indirect, antibody, B cell, repertoire, high-throughput DNA sequencing

Abbreviations used : CDR3, FR, IGH


Plan


 Supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIAID) grants 1U19AI0420901 (S.D.B., PD) and U19AI090019 (M.M.D., PI; S.D.B., PD) and NIH/National Center for Research Resources CTSA award UL1 RR025744.
 Disclosure of potential conflict of interest: C. L. Dekker has received research support from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID; U19A1057229 [M. M. Davis] and U19AI090019 [M. M. Davis]), EMMES (NIH/VRC prime; VRC 703 [seasonal flu DNA vaccine]) and has received consultancy fees from Pfizer. M. M. Davis has received research support, payment for writing/reviewing the manuscript, and Provision of writing assistance, medicines, equipment, or administrative support from the NIH (U19 AI090019). S. D. Boyd has received research support from NIH/NIAID, Department of Defense, and Ellison Medical Foundation; has received consultancy fees from ImmuMetrix; has received lecture fees from the Clinical Immunology Society, the JASON program, the International Society of Laboratory Hematology, the Banff International Research Station, Keystone Symposia, Cold Spring Harbor Laboratories, Brigham Young University, the University of Nebraska, the XXI Mexican Congress of Immunology, the Hudson Alpha Institute, the University of Cincinnati, and the Illumina Scientific Advisory Board; has a US-TPO patent related to DNA sequence interpretation; and has stock in CareDx and Lineage Biosciences. The rest of the authors declare that they have no relevant conflicts of interest.


© 2015  American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
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P. 579 - février 2016 Retour au numéro
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